Optogenetic inhibition of the dorsal hippocampus CA3 region during early-stage cocaine-memory reconsolidation disrupts subsequent context-induced cocaine seeking in rats.

The dorsal hippocampus (DH) is key to the maintenance of cocaine memories through reconsolidation into long-term memory stores after retrieval-induced memory destabilization. Here, we examined the time-dependent role of the cornu ammonis 3 DH subregion (dCA3) in cocaine-memory reconsolidation by utilizing the temporal and spatial specificity of optogenetics. eNpHR3.0-eYFP- or eYFP-expressing male Sprague-Dawley rats were trained to lever press for cocaine infusions in a distinct context and received extinction training in a different context. Rats were then re-exposed to the cocaine-paired context for 15 min to destabilize cocaine memories (memory reactivation) or remained in their home cages (no-reactivation). Optogenetic dCA3 inhibition for one hour immediately after memory reactivation reduced c-Fos expression (index of neuronal activation) in dCA3 stratum pyramidale (SP) glutamatergic and GABAergic neurons and in stratum lucidum (SL) GABAergic neurons during reconsolidation. Furthermore, dCA3 inhibition attenuated drug-seeking behavior (non-reinforced lever presses) selectively in the cocaine-paired context three days later (recall test), relative to no photoinhibition. This behavioral effect was eNpHR3.0-, memory-reactivation, and time-dependent, indicating a memory-reconsolidation deficit. Based on this observation and our previous finding that protein synthesis in the DH is not necessary for cocaine-memory reconsolidation, we postulate that recurrent pyramidal neuronal activity in the dCA3 may maintain labile cocaine memories prior to protein synthesis-dependent reconsolidation elsewhere, and SL/SP interneurons may facilitate this process by limiting extraneous neuronal activity. Interestingly, SL c-Fos expression was reduced at recall concomitant with impairment in cocaine-seeking behavior, suggesting that SL neurons may also facilitate cocaine-memory retrieval by inhibiting non-engram neuronal activity.